Synaptogenesis entails orchestrated changes to the structure of both presynaptic and postsynaptic elements. The present application focuses on two Drosophila genes identified in our mutant screens as having a role in synaptogenesis. The first of these is a member of the ?2? family of proteins. Previously considered to be only auxiliary subunits of CaV channels, we have found that they have a novel function in synaptogenesis that is unrelated to their channel functions. Mutants lacking ?2?-3 from their motorneurons do not form any synaptic boutons at the neuromuscular junction, although axon outgrowth, guidance, and target recognition proceed normally and synaptic vesicles and active zones are present. The defect is selectively in bouton formation. We propose to characterize the defect in these mutants, compare different members of the ?2? family for their competence in the two aspects of their function: channel expression and bouton formation, and perform structure/function studies and protein chemistry to probe the mechanism of ?2? function at the fly NMJ. The second focus of the application is on the role of importins in mediating synapse to nucleus signaling postsynaptically at the fly NMJ. At this synapse, a novel wg/WNT signaling pathway has been described in which the C-terminus of Frizzled2 receptors is cleaved from the receptor and can translocate to muscle nuclei. We have uncovered two importins (?11 and ?2) that are required for this C-terminal fragment to enter the nucleus. We propose to clarify the involvement of the importins in this pathway and to use the mutants to determine the developmental significance of this putative signaling pathway. Relevance: The formation of proper synapses is crucial for brain development and defects in this process are likely to account for many forms of neurological developmental delays and cognitive disorders. Synapse to nucleus signaling is known to be important for synaptic plasticity as well, particularly for forms of long-term memory.

Public Health Relevance

This proposal exams two proteins that we have found to have crucial roles in synapse formation. The formation of proper synapses is essential for brain development and defects in this process are likely to account for many forms of neurological developmental delays and cognitive disorders. Synapse to nucleus signaling is known to be important for synaptic plasticity as well, particularly for forms of long-term memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041062-13
Application #
8269725
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
2000-04-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
13
Fiscal Year
2012
Total Cost
$503,217
Indirect Cost
$214,012
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Lee, GaYoung; Schwarz, Thomas L (2016) Filamin, a synaptic organizer in Drosophila, determines glutamate receptor composition and membrane growth. Elife 5:
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Murthy, Mala; Teodoro, Rita O; Miller, Tamara P et al. (2010) Sec5, a member of the exocyst complex, mediates Drosophila embryo cellularization. Development 137:2773-83
Higashi-Kovtun, Misao E; Mosca, Timothy J; Dickman, Dion K et al. (2010) Importin-beta11 regulates synaptic phosphorylated mothers against decapentaplegic, and thereby influences synaptic development and function at the Drosophila neuromuscular junction. J Neurosci 30:5253-68
Mosca, Timothy J; Schwarz, Thomas L (2010) The nuclear import of Frizzled2-C by Importins-beta11 and alpha2 promotes postsynaptic development. Nat Neurosci 13:935-43
Mosca, Timothy J; Schwarz, Thomas L (2010) Drosophila Importin-?2 is involved in synapse, axon and muscle development. PLoS One 5:e15223
Kurshan, Peri T; Oztan, Asli; Schwarz, Thomas L (2009) Presynaptic alpha2delta-3 is required for synaptic morphogenesis independent of its Ca2+-channel functions. Nat Neurosci 12:1415-23
Dickman, Dion K; Kurshan, Peri T; Schwarz, Thomas L (2008) Mutations in a Drosophila alpha2delta voltage-gated calcium channel subunit reveal a crucial synaptic function. J Neurosci 28:31-8
Miech, Claudia; Pauer, Hans-Ulrich; He, Xi et al. (2008) Presynaptic local signaling by a canonical wingless pathway regulates development of the Drosophila neuromuscular junction. J Neurosci 28:10875-84
Khodosh, Rita; Augsburger, Adela; Schwarz, Thomas L et al. (2006) Bchs, a BEACH domain protein, antagonizes Rab11 in synapse morphogenesis and other developmental events. Development 133:4655-65

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